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Wednesday, December 21, 2011

Good crud -- antivirals

The development of antiviral agents to combat viral infections from the common cold to HIV, hepatitis, SARS, Ebola, and other lethal diseases has proven to be elusive to date. Such an agent would be an invaluable contribution to the world's armamentarium against disease. And now it may be that the world is on the verge of getting such an agent. Last year, Leo James, an immunologist at Cambridge reported in PNAS that his lab had found that antibodies can make their way into cells and destroy the virus before it harms the cell or causes illness. This was treated as great news for the possible development of antivirals, though it was early days, and of course much more work is needed.

Then, Todd Rider, at MIT, published a paper in PLoS One in July that reported progress on a treatment that takes advantage of the double stranded nature of RNA viruses, and the ability of cells to kill themselves when they detect that they've been infected by a virus.

We have developed a new broad-spectrum antiviral approach, dubbedDouble-stranded RNA (dsRNA)ActivatedCaspaseOligomerizer (DRACO) that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.

Why this was published in PLoS One, which is in many senses not really a fully peer reviewed journal, if it is so important isn't clear. Maybe it was rejected by more noted journals, or maybe the authors believe in the public library concept, or they want quick publication without the usual delays and hassles with nit-picking referees. In any case, why is the BBC just getting around to reporting this now? Because they've just done a radio segment on the development of antivirals, including an interview with Rider, highlighting his work.

Viruses are difficult to stop because they are complete parasites, and so much of how they work is identical to how our own cells work. Bacteria are easier targets because they are so different from ourselves, and so destroying them doesn't pose the same kind of risk to our own cells that targeting viruses does.

A number of labs are currently working on antivirals, from somewhat different angles. Peter Palese at Mt Sinai has found a compound which is active at least against influenza, and perhaps other respiratory viruses, though in principle, the list could be longer. Every cell needs pyrimidines to make nucleic acids -- if you reduce the pool of pyrimidines, viruses won't be able to replicate. Palese has identified a compound that acts to reduce that pool, which results in a lower viral load and absence of clinical disease, at least for the flu. Why that wouldn't harm the host cells for the same reason isn't clear (to us, who aren't experts in this area by any means).

A different agent looks to be effective against a large number of viruses. Benhur Lee at UCLA has identified a compound that seemed to be effective against poxes, RNA viruses, DNA viruses, and many others. These are lipid envelope viruses; Lee's agent attacks the viral lipid membrane, disarming at least (or only, it's not yet clear) this type of virus.

But Todd Rider suggests that his drug, or DRACO (yes, you are supposed to think of "draconian") will be able to treat all viral infections, without harming uninfected cells. Cells have enzymes that can detect long dsRNA -- when they detect it, they fight the virus off. But, some viruses can outsmart that system, so Rider has wired together the protein that recognizes dsRNA with a caspase, a protein that triggers apoptosis, or cell suicide. When it finds the dsRNA, it will activate the caspase, causing the infected cell to destroy itself.

Will this method become clinically useful? Other immunologists caution that success in the laboratory is a far cry from success in infected humans. Rider recognizes that he has a lot more work to do, but he says that so far no one has offered a reason why his antiviral approach isn't going to work. The potential seems to be there. Of course, side effects, both foreseen and unforeseen, are a potential risk, as with any new way we find to mess with biology, but this all sounds like progress on an important scale.

If one or more antiviral agent is on the horizon, it is in part due to increased understanding of viruses at the genetic level. This we would say is a laudable use of genetic knowledge and technology. It may be that 90% of the work will turn out to be crud, but this is the kind of generation of crud that seems to us to be justified. And the ubiquity and importance to humans and our pets and food sources, of better control of viruses means this kind of work could be as important as most of us (vainly) claim their (our) work to be.

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